Classifications

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  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
  • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
  • C07C69/734—Ethers
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  • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
  • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
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  • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
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  • C07C205/34—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms of the carbon skeleton
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  • C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
  • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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  • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
  • C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
  • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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  • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
  • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
  • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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  • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
  • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
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  • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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  • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
  • C07C323/19—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with singly-bound oxygen atoms bound to acyclic carbon atoms of the carbon skeleton
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  • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
  • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
  • C07C405/0058—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a not condensed ring different from a five-membered ring
  • C07C405/0066—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a not condensed ring different from a five-membered ring to a six-membered ring
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  • C07C59/40—Unsaturated compounds
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  • C07C59/40—Unsaturated compounds
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  • C07C59/40—Unsaturated compounds
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• This invention is related to phenylalkan(en)oic acids which are useful for medicines.
• this invention is related to:
• Arachidonic acid is metabolized by the action of lipoxygenase, e.g. 5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase, to 5-hydroperoxyeicosatetraenoic acid (abbreviated as HPETE hereinafter), 12-HPETE and 15-HPETE, respectively.
• lipoxygenase e.g. 5-lipoxygenase, 12-lipoxygenase, and 15-lipoxygenase
• HPETE 5-hydroperoxyeicosatetraenoic acid
• HPETEs are converted into 5-hydroxyeicosatetraenoic acid (abbreviated as HETE hereinafter), 12-HETE and 15-HETE, respectively, by the action of peroxidase which convert a hydroperoxy group to a hydroxy group.
• LTA4 is also produced from 5-HPETE.
• LTA4 is converted into LTB 4 and LTC 4 .
• LTC4 is converted into LTD4 by the action of ⁇ -glutamyl transpeptidase.
• LTD4 is metabolized to LTE 4 (see Biochem. Biophys. Res. Commun., 91 , 1266 (1979) and Prostaglandins, 19 (5) , 645 (1980)).
• LTB4 has been gradually identified recently. Namely, it as been identified that LTB4 having the following structure: (wherein the double bonds between 6th- and 7th- carbon, 8th- and 9th-carbon, 10th- and 11th- carbon and 14th- and 15th-carbon, are Z, E, E and Z, respectively), possesses a powerful action of polymorphonuclear leukocytes (PMNLs) accumulation and PMNLs adhesion, and PMNLs degranulation (see Nature, 286, 264 (1980), Proc. Nat. Acad. Sci. USA, 78 , 3887 (1981) and J.Biol. Chem., 256, 5317 (1981)). Moreover it has been considered that LTB4 promotes the release of arachidonic metabilites by attacking various cells as it has the powerful action like calcium ionophore (see J. Biol. Chem., 257 , 4746 (1982)).
• PMNLs polymorphonuclear leukocytes
• LTB4 in high concentration has been detected at the sites of various inflammation, for example, rheumatism, spinal arthritis (see Lanestein L.B., Shapleigh, C. and Goetzl, E.J. (1980) J.Clin. Invest., 66 , 1166-1170), gout (Rae, S.A., Davidson, E.M. and Smith, M.J.H. (1982) Lancet II 1122-1123), psoriasis (see Grabbe, J., Czarnetzki, B.M., Rosenbach, T. and Mardin, M. (1984) J. Invest. Dermatol., 82 , 477-479), ulceractive colitis (see Sharon, P. and Stension, W.F.
• the antagonistic agents on LTB 4 are considered to be useful as anti-inflammatory agents and antiallergic agents.
• the present invention is related to
• alkyl, alkoxy, alkenyl, alkenyloxy, alkylthio, alkenylthio, alkylene and alkenylene groups mean straight-chain or branched-chain alkyl, alkoxy, alkenyl, alkenyloxy, alkylthio, alkenylthio, alkylene and alkenylene groups, respectively, and the double-bond in alkenylene, alkenyl, alkenyloxy and alkenylthio groups include E, Z and the mixture of E and Z.
• the present invention includes the isomers caused by existing asymmetrical carbon atoms.
• C1-13 alkylene group shown by W are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, tridecamethylene group and isomers thereof.
• C1-4 alkyl group shown by R', R 2 , substituent in R 6 , and R 7 are methyl, ethyl, propyl, butyl group and isomers thereof.
• 4-7 membered, saturated or unsaturated, mono-cyclic hetero ring containing one nitrogen as a hetero atom shown by R' are, for example, pyrrole, pyridine ring and partially or fully saturated rings thereof, such as pyrrolidine. These rings may be substituted by one oxo group.
• 4-7 membered, saturated or unsaturated, mono-cyclic hetero ring containing two or three of nitrogen and sulfur in total, shown by R 2 are, for example, thiazole, isothiazole, thiadiazoline ring and partially or fully saturated rings thereof.
• saturated or unsaturated, 7-14 membered, bi- or tri-cyclic hetero ring containing one nitrogen as a hetero atom, shown by two R 2 , taken together with a nitrogen to which they are attached are, for example, indole, isoindole, quinoline, isoquinoline, carbazole, acridine ring and partially or fully saturated rings thereof.
• Saturated or unsaturated, 4-7 membered, mono-cyclic hetero ring containing two or three of nitrogen and oxygen in total, shown by two R 2 , taken together with a nitrogen are, for example, oxazole, isooxazole, furazan ring and partially or fully saturated rings thereof and morpholine ring.
• C3-11 alkylene and alkenylene groups shown by Z are trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene group and isomers thereof and the groups containing 1 to 3 of double bonds therein.
• C1-8 alkyl group shown by R 3 are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.
• C1-8 alkoxy group shown by R 3 are methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof.
• C1-8 alkylthio group shown by R 3 are methylthio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio group and isomers thereof.
• C2-8 alkenyl group shown by R 3 are the groups containing 1 to 3 of double bonds in ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl group and isomers thereof.
• C2-C8 alkenyloxy group shown by R 3 are the groups containing 1 to 3 of double bonds in ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy group and isomers thereof.
• C2-C8 alkenylthio group shown by R 3 are the groups 1 to 3 of double bonds in ethylthio, propylthio, butylthio, pentylthio, hexylthio, heptylthio, octylthio group and isomers thereof.
• Halogen shown by R 3 are, fluorine, chlorine, bromine and iodine atom.
• C3-22 alkyl group shown by Z, taken together with B are propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl group and isomers thereof.
• C1-7 alkylene group shown by R 4 are methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene group and isomers thereof.
• C1-12 alkyl group shown by R 5 are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl group and isomers thereof.
• C2-12 alkenyl group shown by R 5 are the groups containing 1 to 3 of double bonds in ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl group and isomers thereof.
• C5-7 cycloalkyl group shown by R 5 are cyclopentane, cyclohexane, cycloheptane.
• C1-4 alkoxy group shown by substituents in R 5 are methoxy, ethoxy, propoxy, butoxy group and isomers thereof.
• C1-7 alkyl group shown by R 6 are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl group and isomers thereof.
• the compounds wherein W represents an alkylene, of the present invention are quite novel in structure. Furthermore, it can not be expected from the information of the related arts that the compounds having these structures, possess an antagonism on leukotriene 6 4 .
• the compounds wherein W represents a phenylene or the group of the formula: of the present invention are also quite novel.
• the compounds of the formula (d) have the structure in which the group corresponding to A in the formula (I) is carbonyl group, and those of the formula (e) have the structure in which the group corresponding to A in the formula (I) is oxy, carbonyl, methylene or hydroxymethylene group.
• the compounds wherein W represents a phenylene or the group of the formula: of the present invention have the group of the formula: -NHCO- or -NHS0 2 - as the group A. Therefore, the compounds of the present invention are quite different from the related arts in structure in that the groups shown by A represent quite different groups.
• Non-toxic and water-soluble salts are preferable.
• Suitable salts are followings: salts of alkaline metal (sodium, potassium etc.), salts of alkaline earth metal (calcium, magnesium etc.), ammonium salts, salts of pharmaceutically acceptable organic amine (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine etc.).
• the compounds of the formula (I), of the present invention may be prepared by
• R 1a is hydrogen, saturated or unsaturated, 4-7 membered mono-cyclic hetero ring containing one nitrogen as a hetero atom, which ring is unsubstituted or substituted by an oxo group, or C1-4 alkyl;
• Z 1 taken together with B I , is C3-22 alkyl;
• Z 2 is C3-11 alkylene or alkenylene;
• B 2 is the group shown by p is 2-8; r is 2 or 3;
• THP is tetrahydropyran-2-yl;
• Ms is mesyl; Ac is acetyl;
• p-TsOH is p-toluenesulfonic acid;
• SO 3 Py is the complex of sulfur trioxide and pyridine;
• DMSO is dimethyl sulfoxide; Py is pyridine;
• DCC 1,3-dicyclohexylcarbodiimide; and the other symbols are the same meanings as described hereinbefore.
• products may be purified by conventional manner. For example, it may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
• the starting materials and each reagents in the present invention are known or may be prepared by the known methods.
• the percentage of inhibition (%) 100 - (Bi/Bo X 100)
• B 1 specific 3 H-LTB 4 binding in presence of antagonist
• Bo specific 3 H-LTB 4 binding in absence of antagonist
• the purified human PMNLs were suspended in Hank's-0.5% BSA medium (pH 7.4) at 1 X 10 7 cells/ml.
• the PMNLs suspentions 200 ⁇ l were preincubated with varying concentrations of tasted compounds for 3 min at 37° C prior to the addition of 10- 8 M solution (10 ml) of LTB 4 in Hank's solution.
• PMNLs aggregation in vitro was performed with a multichannel platelet aggregometer. Aggregation was detected as change in light transmission with an aggregometer.
• the toxicity of the compounds, of the present invention were very low.
• the acute toxicity (LDso) of the compounds in Example 30 and 31 (a) are 3.9 g/kg and 2.2 g/kg, respectivity, in oral administration and 175 mg/kg and 260 mg/kg, respectivity, in intravenous administration in mouse. Accordingly, it was confirmed that the compounds of the present invention were useful for pharmaceutical agent.
• the compounds of the formula (I), of the present invention are useful for prevention and/or treatment for allergic dermatosis, rheumatism, gout, psoriasis, arthritis, trychophytosis, cardiac infarction etc. in mammals including human beings since they possess an antagonism on LTB4
• the compounds, of the formula (I), of the present invention and non-toxic salts thereof may be normally by administered systemically or partially usually by oral or parenteral administration.
• the doses to be administered are determined depending upon age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment etc..
• the doses per person per dose are generally between 1 mg and 1000 mg, by oral administration, up to several times per day, and between 1 mg and 100 mg, by parenteral administration up to several times per day, or contineous administration between 1 and 24 hrs. per day from vein.
• the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
• compositions of the present invention When administration of the compounds of the present invention, it is used as solid compositions, liquid compositions or other compositions for oral administration, as injections, liniments or suppositories etc. for parenteral administration.
• Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules.
• Capsules contain hard capsules and soft capsules.
• one or more of the active compound(s) is or are, admixed with at least one inert diluent (lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate etc.)
• the compositions may also comprise, as is normal practice, additional substances other than inert diluents: e.g. lubricating agents (magnesium stearate etc.), disintegrating agents (cellulose calcium glycolate etc.), stabilizing agent (lactose etc.), and assisting agent for dissolving (glutamic acid, asparaginic acid etc.).
• the tablets or pills may, if desired, be coated with film of gastric or enteric material (sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate etc.), or be coated with more than two films. And further, it may be include capsules of absorbable materials such as gelatin.
• film of gastric or enteric material sucrose, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate etc.
• it may be include capsules of absorbable materials such as gelatin.
• Liquid compositions for oral administration include pharmaceutically-acceptable solutions, emulsions, suspensions, syrups and elixirs.
• one or more of the active compound(s) is or are comprise in inert diluent(s) commonly used in the art (purified water, ethanol etc.).
• compositions may also comprise adjuvants (wetting agents, suspending agent etc.), sweetening agents, flavouring agents, perfuming agents and preserving agent.
• compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s).
• Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents (sodium sulfite etc.), isoionic bufier (sodium chloride, sodium citrate, citric acid etc.)
• stabilizing agents sodium sulfite etc.
• isoionic bufier sodium chloride, sodium citrate, citric acid etc.
• Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions.
• one more of active compound(s) is or are admixed at least one of inert aqueous diluent(s) (distilled water for injection, physiological salt solution etc.) or inert non-aqueous diluent(s) (propylene glycol, polyethylene glycol, olive oil, ethanol, POLYSOLBATE80 (registered trade mark) etc.).
• Injections may comprise aditional other than inert diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent (lactose etc.), assisting agents such as assisting agents for dissolving (glutamic acid, asparaginic acid etc.).
• inert diluents e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agent (lactose etc.), assisting agents such as assisting agents for dissolving (glutamic acid, asparaginic acid etc.).
• They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They also be manufactures in the form of sterile solid compositions, for example, by freeze-drying, and which can be dissolved in sterile water or some other sterile diluents for injection immediately before used.
• compositions for parenteral administration include liquids for external use, and endermic liniments (ointment etc.), suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by known methods.
• the compounds of the formula (I) can be named as derivatives of an alkan(en)oic acid with the numbering of the benzene ring as follows:
• the above compound can be called 3-(1-substituted-(3 or 4)-substitutedbenzen-2-yl)propionic acid.
• Sodium hydride (content:62%, 3.3g) was suspended in tetrahydrofuran (30 ml). The suspension was ice-cooled in an atmosphere of argon gas. A solution of t-butyl diethylphosphonoacetate (20.9 g) in tetrahydrofuran (20 ml) was added to the suspension. The mixture was stirred for 15 min. at room temperature. A solution of 2-hydroxy-5-nitrobenzaldehyde (6.6 g) in tetrahydrofuran (20 ml) was gradually added to the mixture often with ice-cooling. The mixture was stirred for 10 min. at room temperature. Acetic acid was gradually added to the mixture until pH of the mixture was down to 5.0.
• the ester (prepared in reference example 2; 6.4 g) was dissolved in methylene chloride (100 ml). Pyridine (5.0 ml) was added to the solution. 4-methoxycarbonylbutanoyl chloride (3.75 ml) was added to the solution with ice-cooling. The mixture was stirred for 10 min. at room temperature. Ice was added to the reaction mixture. The mixture was extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid, saturated aqueous solution of sodium bicarbonate, followed by saturated brine, dried over anhydrous magnesium sulfate and evaporated.
• Phenol (580 mg; prepared in reference example 3) and sodium hydride (content : 62%, 62 mg) were dissolved in dried dimethylformamide (2 ml). The solution was stirred at room temperature in an atmosphere of argon gas. A solution of 6-(p-methoxyphenyl)-5E-hexenol methanesulfonate (450 mg) in dried dimethylformamide (1 ml) was added to the solution. The mixture was stirred for 2 hr. at 60 C. The reaction mixture was poured into a mixture of ice and 1 N hydrochloric acid (10 ml). The mixture was extracted with diethyl ether - ethyl acetate (1 : 1).
• the ester (265 mg; prepared in reference example 4) was dissolved in a mixture of methanol (3 ml) and tetrahydrofuran (2 ml). A 1 N aqueous solution of sodium hydroxide (1.0 ml) was added to the solution. The solution was stirred for 3 hr at room temperature. The reaction solution was diluted with water. 1 N hydrochloric acid (1.5 ml) was added to the solution. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated to give the residue contained the title compound having the following physical data. The residue was used in next reaction without purification. TLC(ethyl acetate) : Rf 0.10.
• the ester (86 mg; prepared in reference example 5) was dissolved in a mixture of dried tetrahydrofuran (1 ml) and triethylamine (44 ⁇ l). Ethyl chloroformate (23 ⁇ l) was gradually added to the solution at -10°C. The solution was stirred for 15 min. at -10° C. Morpholine (generally 0.5 ml) was added to the solution. The mixture was stirred for 30 min. at 0° C and then for 30 min. at room temperature. The reaction mixture was poured to a mixture of ice and 2N hydrochloric acid (10 ml). The mixture was extracted with ethyl acetate.
• the ester (210 mg ; prepared in reference example 5) was dissolved in tetrahydrofuran (2 ml). Triethylamine (56 ⁇ l) was added to the solution. Ethyl chloroformate (35 ml) was added to the solution at -10°. The solution was stirred for 10 min. at -10°C. Sodium borohydride (25 mg) and methanol (0.3 ml) was gradually added to a half quantity of the reaction solution. The solution was stirred for 15 min.. The reaction solution was diluted with ethyl acetate.
• the trifluoroacetoamide (5.3 g), which was prepared with using the compound prepared in reference example 17 by the same procedure as reference example 4 was dissolved in a mixture of methanol (30 ml) and water (5 ml). Anhydrous potassium carbonate (2.8 g) was added to the solution. The mixture was stirred at room temperature a whole day and night. Water (100 ml) was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate (200 ml x 2). The extract was washed with brine, dried over anhydrous magnesium sulfate and then evaporated.
• the ester (176 mg) prepared in reference example 18 was dissolved in a mixture of methylene chloride (3 ml) and triethylamine (0.29 ml). Methanesulfonyl chloride (35 ⁇ l) was added to the solution at 0°C. The solution was stirred for 30 min. Acetyl chloride (0.12 ml) was added to the reaction solution. The mixture was refluxed for 10 min. The reaction mixture was poured into a mixture of ice and 1 N hydrochloric acid (10 ml). The reaction mixture was extracted with ethyl acetate (80 ml). The extract was washed with water, followed by brine, dried over anhydrous magnesium sulfate and evaporated.
• the ester (158 mg) prepared in reference example 18 was dissolved in a mixture of methylene chloride (3 ml) and triethylamine (0.15 ml). Methanesulfonyl chloride (72 ⁇ l) was added to the solution at room temperature. The solution was stirred for 1 hr. The reaction solution was poured into a mixture of ice and 1 N hydrochloric acid (10 ml). The reaction mixture was extracted with ethyl acetate (80 ml). The extract was washed with water, followed by brine, dried over anhydrous mangesium sulfate and then evaporated.
• the t-butyl ester (950 mg), which was prepared with using the ester prepared in reference example 18 by the same procedure as reference example 3 (with the proviso that the corresponding sulfonyl chloride was used instead of 4-methoxycarbonylbutanoyl chloride) - reference example 5, was dissolved in a mixture of tetrahydrofuran (15 ml) and triethylamine (0.69 ml). Ethyl chloroformate (0.24 ml) was gradually added to the solution at 15° C in an atmosphere of argon gas. The solution was stirred for 10 min at -15° C and then for 30 min at 0°C.
• p-Toluenesulfonic acid (15 mg) was added to the solution.
• the solution was stirred for 40 min at room temperature. Few drops of triethylamine was added to the reaction solution.
• the reaction mixture was evaporated.
• TLC(ethyl acetate : n-hexane 1 : 2) : Rf 0.10; MS : m/z 419 (M ), 363, 277, 259, 231.
• 2,5-Dimethoxybenzaldehyde (1.7 g) was dissolved in pyridine (10 ml). Piperidine (0.2 ml) and malonic acid (2.0 g) were added to the solution. The solution was stirred for 1 hour at 85°C and then for 3 hr. at 110°C. The solution was cooled. Water (80 ml) was added to the solution. Conc. hydrochloric acid was added to the solution until pH of the solution was down to about 2. The crystals were deposited. The crystals were separated from the solution by filtration, washed with water and dried to give the title compound (1.97 g) having the fo.owing physical data.
• 6-Hydroxycoumarin (405 mg; prepared in reference example 25) was dissolved in dry dimethylformamide (6 ml). Sodium hydride (60 mg) was added to the solution. The mixture was reacted for 15 min. Ethyl 5-bromopentanoate (0.48 ml) was added dropwise to the reaction solution. The mixture was stirred for 1 hr at 60° C. Ice-water was added to the reaction solution. The mixture was acidified with 1N hydrochloric acid. The mixture was extracted with ether. The extract was washed with water, dried anhydrous magnesium sulfate and then evaporated.
• the dicarboxylic acid (1.72 g) prepared in reference example 29 was dissolved in a mixture of benzene (100 ml) and tetrahydrofuran (2 ml).
• Dowex 50W x 8 (H form)(about 10 ml) was added to the solution.
• the mixture was refluxed for 2 hr..
• the reaction solution was filtered to remove Dowex.
• the filtrate was evaporated to give the residue (1.28 g) contained the title compound having the following physical data.
• the residue was used in next reaction without purification.
• TLC(chloroform : methanol 10 : 1) : Rf 0.49; MS : m/z 248 (M 230.
• a carboxylic acid which was prepared with using the lactone prepared in reference example 30 by the same procedure as reference example 6 (with the proviso that dimethylamine was used instead of morpholine) - example 5, was dissolved in ethanol (5 ml). Conc. sulfuric acid (about 0.1 ml) was added dropwise to the solution. The solution was stirred for 1.5 hr. at 60° C. The reaction solution was diluted with ethyl acetate. The diluted solution was washed with saturated aqueous solution of sodium bicarbonate, followed by saturated brine, dried over anhydrous magnesium sulfate and evaporated.
• a dicarboxylic acid (6.6 g), which was prepared with using the ester prepared in reference example 28 by the same procedure as reference example 5, was dissolved in acetic acid (10 ml). 47% hydrobromic acid (30 ml) was added to the solution. The mixture was refluxed all night. The reaction solution was evaporated. The residue was diluted with ethyl acetate. The diluted solution was washed with saturated brine, dried over magnesium sulfate and then evaporate. The residue was recrystallized from ethyl acetate to give the title compound (915 mg) having the following physical data. MS : m/z 280 (M 262.
• Anhydrous 2-methoxyphthalic acid (640 mg), which was prepared with using anhydrous 2-hydroxyphthalic acid by the same procedure as reference example 12, was suspended in tetrahydrofuran (20 ml). Acetic acid (430 mg) and sodium borohydride (135 mg) were added to the suspension. The mixture was stirred for 30 min. at room temperature and for 2 hr. at 50 °C. The reaction solution was cooled. 1 N hydrochloric acid (7 ml) was added to the cooled solution. The solution was stirred for 15 min. The reaction solution was evaporated.
• the phthalide (346 mg) prepared in reference example 33 was dissolved in toluene (20 ml). The solution was cooled to -78° C. A 1.76N solution of diisobutylaluminum hydride (DIBAL) in toluene (1.43 ml) was added dropwise to the cooled solution. The mixture was stirred for 30 min. at -78° C. Methanol (0.2 ml) was added to the reaction solution to decompose the excess DIBAL. Water was added to the reaction solution. A temperature of the solution was up to room temperature. The solution was stirred for 30 min. at room temperature.
• DIBAL diisobutylaluminum hydride
• Methyl 6-[2-(2-ethoxycarbonylethyl)-3-methoxyphenyl]-hexanoate which was prepared with using the compound prepared in reference example 35 by the same procedure as reference example 12 ⁇ reference example 2 - reference example 14 ⁇ reference example 1 (with the proviso that ethyl diethylphosphonoacetate was used instead of t-butyl diethylphosphonoacetate) - reference example 2, and pyridine hydrochloride were reacted for 2 hr. at 190°C. The reaction mixture was cooled. 1 N hydrochloric acid was added to the mixture. The mixture was extracted with ethyl acetate.
• the reaction mixture was added to a saturated aqueous solution of ammonium chloride.
• the mixture was extracted with diethyl ether.
• the extract was washed with water, dried over anhydrous magnesium sulfate and evaporated.
• IR(cm -1 ) ⁇ 3307, 2932, 1723, 1609, 1510, 1245, 1116, 1032.
• the title compound, of the present invention having the following physical data was obtained with using a tert-butyl ester, which was prepared with using the tert-butyl ester prepared in reference example 17 by the same procedure as reference example 4 (with the proviso that the corresponding appropriate methanesulfonate was used instead of 6-(p-methoxyphenyl)-5E-hexenol methanesulfonate) - reference example 18 - reference example 3 (with the proviso that the corresponding appropriate sulfonyl chloride was used instead of 4-methoxycarbonylbutanoyl chloride), by the same procedure as example 1.
• the title compound, of the present invention having the following physical data was obtained with using 6-hydroxycoumarin prepared in reference example 25 by the same procedure as reference example 26 (with the proviso that N,N-dimethyl-5-bromopentanamide was used instead of ethyl 5-bromopentanoate) - reference example 27 - reference example 2- reference example 10 - reference example 23 - reference example 14 - reference example 15 - reference example 16 - reference example 5 and then purification by column chromatography on silica gel.
• the title compound, of the present invention having the following physical data was obtained with using an ester, which was prepared with using 3-(1-methoxybenzen-2-yl)propionic acid by the same procedure as reference example 12 - reference example 28 (with the proviso that methyl 5-(chloroformyl)pentanoate was used instead of methyl 4-(chloroformyl)butyrate) - reference example 16 - reference example 29 ⁇ reference example 30 - reference example 31, by the same procedure as example 18.
• the title compound, of the present invention having the following physical data was obtained with using a dicarboxylic acid, which was prepared with using 3-(1-methoxybenzen-2-yl)propionic acid by the same procedure as reference example 12 - reference example 28 (with the proviso that methyl 5-(chloroformyl)-pentanoate was used instead of methyl 4-(chloroformyl)-butyrate) - reference example 5 - reference example 32, by the same procedure as example 19.
• the title compound, of the present invention having the following physical data was obtained with using the ethyl ester prepared in reference example 31 by the same procedure as reference example 10 ⁇ reference example 23 - reference example 14 - reference example 15 -reference example 16 - reference example 5 and then purification by column chromatography on silica gel.
• TLC(ethyl acetate) Rf 0.42;
• IR(cm -1 ) ⁇ 3402, 2927, 2856, 1728, 1626, 1504, 1468, 1402, 1251, 1161, 1121, 1058, 971, 908, 810, 723.
• the title compound, of the present invention having the following physical data was obtained with using a dicarboxylic acid, which was prepared with using 3-(1-methoxybenzen-2-yl)propionic acid by the same procedure as reference example 12 ⁇ reference example 28 (with the proviso that methyl 5-(chloroformyl)-pentanoate was used instead of methyl 4-(chloroformylbutyrate) ⁇ reference example 29, by the same procedure as example 24.
• the title compound, of the present invention having the following physical data was -obtained with using a dicarboxylic acid, which was prepared with using 3-(1-methoxybenzen-2-yl)propionic acid by the same procedure as reference example 12 ⁇ reference example 28 (with the proviso that methyl 4-(chloroformyl)pentanoate was used instead of methyl 4-(chloroformyl)butyrate) - reference example 5 - reference example 32, by the same procedure as example 27.
• a residude was obtained with using the carboxylic acid prepared in reference example 40 by the same proceure as reference examples 25 ⁇ reference example 27 ⁇ reference example 31 - reference example 4 - reference example 5.

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• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pulmonology (AREA)
• Immunology (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyrrole Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
• Indole Compounds (AREA)
• Thiazole And Isothizaole Compounds (AREA)
• Other In-Based Heterocyclic Compounds (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

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• 1990
  • 1990-05-07 CA CA002019335A patent/CA2019335C/fr not_active Expired - Fee Related
  • 1990-05-15 JP JP2123146A patent/JPH0739369B2/ja not_active Expired - Fee Related
  • 1990-05-16 DK DK94118144T patent/DK0652208T3/da active
  • 1990-05-16 EP EP94118144A patent/EP0652208B1/fr not_active Expired - Lifetime
  • 1990-05-16 DE DE69023960T patent/DE69023960T2/de not_active Expired - Fee Related
  • 1990-05-16 EP EP90109294A patent/EP0405116B1/fr not_active Expired - Lifetime
  • 1990-05-16 ES ES94108324T patent/ES2102097T3/es not_active Expired - Lifetime
  • 1990-05-16 DE DE69030202T patent/DE69030202T2/de not_active Expired - Fee Related
  • 1990-05-16 DE DE69031959T patent/DE69031959T2/de not_active Expired - Fee Related
  • 1990-05-16 DK DK90109294.0T patent/DK0405116T5/da active
  • 1990-05-16 AT AT94108324T patent/ATE150006T1/de not_active IP Right Cessation
  • 1990-05-16 AT AT90109294T patent/ATE131154T1/de not_active IP Right Cessation
  • 1990-05-16 EP EP94108324A patent/EP0619296B1/fr not_active Expired - Lifetime
  • 1990-05-16 AT AT94118144T patent/ATE162181T1/de not_active IP Right Cessation
  • 1990-05-16 DK DK94108324.8T patent/DK0619296T3/da active
  • 1990-05-16 ES ES90109294T patent/ES2083396T3/es not_active Expired - Lifetime
  • 1990-05-16 ES ES94118144T patent/ES2114117T3/es not_active Expired - Lifetime
  • 1990-05-17 US US07/524,521 patent/US5086065A/en not_active Expired - Lifetime
  • 1990-05-18 KR KR1019900007107A patent/KR0143404B1/ko not_active Expired - Fee Related
• 1991
  • 1991-09-13 US US07/760,043 patent/US5155104A/en not_active Expired - Fee Related
• 1993
  • 1993-05-07 JP JP5131187A patent/JPH0819040B2/ja not_active Expired - Lifetime
• 1995
  • 1995-12-21 GR GR950403640T patent/GR3018510T3/el unknown
• 1997
  • 1997-03-13 GR GR970400301T patent/GR3022801T3/el unknown
  • 1997-12-12 KR KR97071141A patent/KR0148212B1/ko not_active Expired - Fee Related
  • 1997-12-12 KR KR97071140A patent/KR0148213B1/ko not_active Expired - Fee Related
• 1998
  • 1998-03-13 GR GR980400536T patent/GR3026351T3/el unknown

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